1,2,3,4-Tetrahydroisoquinolines derivatives as urotensin II receptor antagonists

ABSTRACT

The invention relates to novel 1,2,3,4-tetrahydroisoquinoline derivatives of formula (I) and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as neurohormonal antagonists especially urotensin II antagonists.

FIELD OF THE INVENTION

The present invention relates to novel 1,2,3,4-tetrahydroisoquinolinederivatives of the general formula 1 and their use as active ingredientsin the preparation of pharmaceutical compositions. The invention alsoconcerns related aspects including processes for the preparation of thecompounds, pharmaceutical compositions containing one or more compoundsof the general formula 1 and especially their use as neurohormonalantagonists.

BACKGROUND OF THE INVENTION

Urotensin II is a cyclic 11-amino acid peptide that has some sequencesimilarity to, but is not homologous with, somatostatin-14. Urotensin IIwas first isolated and sequenced from fish spinal cord (Bern H A,Pearson D, Larson B A, Nishioka R S. Neurohormones from fish tails: thecaudal neurosecretory system. I. “Urophysiology” and the caudalneurosecretory system of fishes. Recent Prog. Horm. Res. (1985) 41,533-552), and has since been found in a wide variety of vertebrate andinvertebrate species. Human urotensin II is synthesized in a prepro-formfrom a single gene located at chromosome 1p36.21, and two cDNA splicevariants which differ in their putative signal peptide sequence havebeen isolated from human colon tumor and human placenta (GenBankAccession Nr. O95399). The putative prohormone convertase dibasiccleavage site is strictly conserved across species. The mature 11-aminoacid peptide contains a C-terminal disulfide-bridged 6-amino acid loopwhich is also strictly conserved, while the N-terminal portion of themature cyclic peptide can vary considerably across species.

Urotensin II exerts potent and complex hemodynamic actions in mammals(Douglas S A, Sulpizio A C, Piercy V, Sarau H M, Ames R S, Alyar N V,Ohlstein E H, Willette R N. “Differential vasoconstrictor activity ofhuman urotensin-II in vascular tissue isolated from the rat, mouse, dog,pig, marmoset and cynomolgus monkey.” Br. J. Pharmacol. (2000) 131,1262-1274. Douglas, S A, Ashton D J, Sauermelch C F, Coatney R W,Ohlstein D H, Ruffolo M R, Ohlstein E H, Alyar N V, Willette R “HumanUrotensin-II is a potent vasoactive peptide: pharmacologicalcharacterization in the rat, mouse, dog and primate.” J. Cardiovasc.Pharmacol. (2000) 36, Suppl 1:S163-6). The peptide effectivelyconstricts isolated mammalian arteries. The potency of vasoconstrictionis an order of magnitude greater than that of endothelin-1. Theseeffects appear to be mediated at least in part via the actions ofurotensin II on a G-protein coupled receptor named GPR-14 or SENR (AmesR S, et al. “Human urotensin-II is a potent vasoconstrictor and agonistfor the orphan receptor GPR14.” Nature. (1999) 401, 282-6. Mori M, SugoT, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y,Kurokawa T, Onda H, Nishimura 0, Fujino M. “Urotensin II is theendogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14)”Biochem. Biophys. Res. Commun. (1999) 265, 123-9. Liu Q, Pong S S, ZengZ, et al. “Identification of urotensin II as the endogenous ligand forthe orphan G-protein-coupled receptor GPR14” Biochem. Biophys. Res.Commun. (1999) 266, 174-178.) GPR14 is expressed in arterial (but notvenous) smooth muscle cells, on atrial and ventricular cardiac myocytes,in pancreas, kidney, and in the brain.

In addition to its vasoconstrictive actions, urotensin II potentlyaffects atrial and ventricular muscle contraction (Russell F D, MolenaarP, and O'Brien D M “Cardiostimulant effects of urotensin-II in humanheart in vitro”. Br J Pharmacol (2001) 132, 5-9).

Urotensin II stimulates cellular proliferation, migration and collagensynthesis in cardiac fibroblasts (Tzandis A, et al., “Urotensin IIstimulates collagen synthesis by cardiac fibroblasts and hypertrophicsignaling cardiomyocytes via G(alpha)q- and Ras-dependent pathways”. J.Am. Coll. Cardiol. (2001) 37, 164A.) and in neonatal myocytes (Zou Y,Nagai R, and Yamazaki T, “Urotensin II induces hypertrophic responses incultured cardiomyocytes from neonatal rats”. FEBS Lett (2001) 508,57-60). Urotensin II is produced by cancer cell lines and its receptoris also expressed in these cells. (Takahashi K, et al., “Expression ofurotensin II and urotensin II receptor mRNAs in various human tumor celllines and secretion of urotensin II-like immunoreactivity by SW-13adrenocortical carcinoma cells”. Peptides (2001) 22, 1175-9).

Urotensin II modulates' glucose-stimulated pancreatic release of insulin(Silvestre R A, et al., “Inhibition of insulin release by urotensin II—astudy on the perfused rat pancreas”. Horm Metab Res (2001) 33, 379-81).

Elevated circulating levels of urotensin II are detected in humanssusceptible to high-altitude pulmonary edema, and in patients awaitingkidney transplantation (Totsune K, et al., “Role of urotensin II inpatients on dialysis”. Lancet (2001) 358, 810-1).

Urotensin II and its receptor are found in spinal cord and brain tissue,and intracerebroventricular infusion of urotensin II into mice inducesbehavioral changes (Gartlon J, et al., “Central effects of urotensin-IIfollowing ICV administration in rats”. Psychopharmacology (Berlin)(2001) 155, 426-33).

Substances with the ability to block the actions of urotensin II areaccordingly expected to prove useful in the treatment of variousdiseases. WO-2001/45694 discloses certain sulfonamides as urotensin IIreceptor antagonists, and their use to treat diseases associated with aurotensin II imbalance. WO-2001/45700 discloses certain pyrrolidines asurotensin II receptor antagonists and their use to treat diseasesassociated with a urotensin II imbalance. WO-2001/45711 disclosescertain pyrrolyl and pyridyl derivatives as urotensin II receptorantagonists and their use to treat diseases associated with a urotensinII imbalance. WO-2002/00606 discloses certain biphenyl compounds usefulas urotensin II receptor antagonists, and WO-2002/02530 also disclosescertain compounds useful as urotensin II receptor antagonists.

The present invention comprises 1,2,3,4-tetrahydroisoquinolinederivatives which are novel compositions of matter and which areurotensin II receptor antagonists. EP 428434 discloses certainalkylureidopyridines as neurokinin and substance P antagonists.WO-99/21835 discloses certain ureidoquinolines as H+-ATPase and boneresorption inhibitors. WO-01/009088 discloses certain substitutedheteroarylureas as inhibitors of the CCR-3 receptor.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula 1,

wherein

X represents —CH₂—, —CH₂CH₂—, —C(CH₃)₂—;

Y represents oxygen, NH;

n represents the numbers 1 or 2;

Z represents quinolin-4-yl which may be mono-substituted with loweralkyl in the positions 2, 6, or 8, or di-substituted with lower alkyl inthe positions 2, 6 or 2,8; [1,8]naphthyridin-4-yl which may besubstituted in position 7 with lower alkyl; pyridin-4-yl which may besubstituted in position 2 with R⁷R⁸N— and additionally in position 6with hydrogen or lower alkyl;

R¹ represents naphthalen-1-yl; naphthalen-2-yl; benzo[1,3]dioxol-5-yl;benzyl, or mono-, di-, or tri-substituted benzyl substituted in thephenyl ring independently with lower alkyl, lower alkyloxy,trifluoromethyl, halogen, cyano; phenyl, or mono-, di- ortri-substituted phenyl, substituted independently with lower alkyl,lower alkyloxy, trifluoromethyl, halogen, cyano;

R² represents hydrogen, lower alkyl, aryl or forms with R¹ a styrylgroup of E or Z geometry, whereby the phenyl ring in the styryl groupmay be mono-, di- or tri-substituted phenyl, substituted independentlywith lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano;

R³, R⁴, R⁵ and R⁶ independently represent hydrogen, cyano, hydroxy,lower alkyloxy, aralkyloxy, lower alkenyloxy, and R⁵ additionallyrepresents R⁷R⁸NCO;

R⁴ and R⁵ together may form with the phenyl ring a five- or asix-membered ring containing one or two oxygen atoms;

R⁷ and R⁸ independently represent hydrogen, lower alkyl, aryl, aralkyl,or together with the N form a pyrrolidine, piperidine, or morpholinering;

and optically pure enantiomers or diastereomers, mixtures of enantiomersor diastereomers, diastereomeric racemates, and mixtures ofdiastereomeric racemates; as well as their pharmaceutically acceptablesalts, solvent complexes, and morphological forms.

In the definitions of the general formula 1 the expression ‘lower alkyl’means straight or branched chain groups with one to seven carbon atoms,preferably 1 to 4 carbon atoms; or cyclic alkyl groups with three to sixcarbon atoms. Preferred examples of lower alkyl groups are methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, n-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

The expression ‘lower alkyloxy’ means a group of the formula loweralkyl-O— in which the term ‘lower alkyl’ has the meaning previouslygiven. Preferred examples of lower alkyloxy groups are methoxy, ethoxy,propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy,cyclopentyloxy, and cyclohexyloxy.

The expression ‘lower alkenyloxy’ means a group of the formula loweralkenyl-O— in which the term ‘lower alkenyl’ means a straight-chain orbranched-chain alkenyl group with 2 to 5 carbon atoms. Preferredexamples of lower alkenyloxy groups are allyloxy or propenyloxy.

The expression ‘aryl’ means a phenyl or naphthyl group which optionallycarries one or more substituents, preferably one or two substituents,each independently selected from cyano, halogen, lower alkyl, loweralkenyl, lower alkyloxy, lower alkenyloxy, trifluoromethyl,trifluoromethoxy, amino, carboxy and the like. Preferred examples ofaryl groups are phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl,4-chlorophenyl, 4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl,2-fluorophenyl, 2-methoxyphenyl, naphthalen-1-yl and naphthalen-2-yl.

The expression ‘alkyloxy’ means a lower alkyl group as previouslydefined in which one hydrogen atom has been replaced by an aryl group aspreviously defined. Preferred examples of aralkyl groups are benzyl andbenzyl substituted in the phenyl ring with hydroxy, lower alkyl, loweralkyloxy or halogen.

The expression ‘aralkyloxy’ means a group of the formula aralkyl-O— inwhich the term ‘aralkyl’ has the meaning previously given. Preferredexamples of aralkyloxy are benzyloxy and phenethyloxy.

The present invention encompasses pharmaceutically acceptable salts ofcompounds of the general formula 1. This encompasses either salts withinorganic acids or organic acids like hydrohalogenic acids, e.g.hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitricacid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid,methylsulfonic acid, p-tolylsulfonic acid and the like or in case thecompound of formula 1 is acidic in nature with an inorganic base like analkali or earth alkali base, e.g. sodium, potassium, or calcium salts,etc.

The present invention encompasses different solvation complexes ofcompounds of general formula 1. The solvation can be effected in thecourse of the manufacturing process or can take place separately, e.g.as a consequence of hygroscopic properties of an initially anhydrouscompound of general formula 1.

The present invention further encompasses different morphological forms,e.g. crystalline forms, of compounds of general formula 1 and theirsalts and solvation complexes. Particular heteromorphs may exhibitdifferent dissolution properties, stability profiles, and the like, andare all included in the scope of the present invention.

The compounds of the general formula 1 might have one or more asymmetriccarbon atoms and may be prepared in form of optically pure enantiomersor diastereomers, mixtures of enantiomers or diastereomers,diastereomeric racemates, and mixtures of diastereomeric racemates. Thepresent invention encompasses all these forms. They are prepared bystereoselective synthesis, or by separation of mixtures in a mannerknown per se, i.e. by column chromatography, thin layer chromatography,HPLC, crystallization, etc.

Preferred compounds of general formula 1 are the compounds of generalformula 2,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Z, and n have the meaning given ingeneral formula 1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 3,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z have the meaning given ingeneral formula 1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 4,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given ingeneral formula 1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 5,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given ingeneral formula 1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 6,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given ingeneral formula 1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 7,

wherein R¹, R³, R⁴, R⁵, R⁶, X, Y, Z, and n have the meaning given ingeneral formula 1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 8,

wherein Ph is phenyl; mono-, di- or tri-substituted phenyl, substitutedindependently with hydrogen, lower alkyl, lower alkyloxy,trifluoromethyl, halogen, or cyano; and R³, R⁴, R⁵, R⁶, X, Y, Z, and nhave the meaning given in general formula 1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 9,

wherein R¹, R², X, Y, Z, and n have the meaning given in general formula1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 10,

wherein R¹, R², X, Y, Z, and n have the meaning given in general formula1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 11,

wherein R¹, R², X, Y, Z, and n have the meaning given in general formula1 above.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 12,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and n have the meaning given ingeneral formula 1.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 13,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and n have the meaning given ingeneral formula 1.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 14,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, Y, and n have the meaninggiven in general formula 1.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 15,

wherein the 1 position of the 1,2,3,4-tetrahydroisoquinoline ring systemhas the R absolute stereochemical configuration, and R¹, R², R³, R⁴, R⁵,R⁶, X, Z, and n have the meaning given in general formula 1.

Another group of preferred compounds of general formula 1 are thecompounds of general formula 16,

wherein R³, R⁴, R⁵, and R⁶ are independently hydrogen or lower alkyloxy;and R¹, R², and Z have the meaning given in general formula 1 above.

Examples of particularly preferred compounds of general formula 1 are:

1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-(2-{1-[2-(4-Fluoro-phenyl)ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(2,4-Difluoro-phenylpethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea

1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea

1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[(E)-2-(2,4-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(2,5-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

1-(2-{6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolinyl)-urea

1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea

1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolinyl-4-urea

1-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea

1-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea

1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea

1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

1-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea

1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

1-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolinyl-4-yl-urea

1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

1-[2-(6,7-Dimethoxy-1-phenoxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea

1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea

1-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl}-3-pyridin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-methyl-quinolin-4-yl)-urea

1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolinyl-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-yl-urea

1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{3-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea

1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea

1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolinyl-4-urea

1-{3-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea

1-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-quinolin-4-yl-urea

1-[2-(1-Benzhydryl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4yl-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

1-{2-[(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid methylamide

1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid propylamide

1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid dimethylamide

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(7-methyl-[1,8]naphthyridin-4-yl)-urea

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea

1-[2-(Benzyl-methyl-amino)-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea

1-[2-(Benzyl-methyl-amino)-6-methyl-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-[2-(methyl-phenyl-amino)-pyridin-4-yl]-urea

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-pyrrolidin-1-yl-pyridin-4-yl)-urea

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methylamino-1-yl-pyridin-4-yl)-urea

Quinolin-4-yl-carbamic acid2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethylester

Quinolin-4-yl-carbamic acid2-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl ester

Quinolin-4-yl-carbamic acid2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethylester

Quinolin-4-yl-carbamic acid3-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester

Quinolin-4-yl-carbamic acid3-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propylester

Quinolin-4-yl-carbamic acid3-[1-(3,4-difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester

Quinolin-4-yl-carbamic acid3-[1-(3,4-dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester

Quinolin-4-yl-carbamic acid3-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester

Because of their ability to inhibit the actions of urotensin II, thedescribed compounds can be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation or otherdisease states associated with the actions of urotensin II. Examples ofsuch diseases are hypertension, atherosclerosis, angina or myocardialischemia, congestive heart failure, cardiac insufficiency, cardiacarrhythmias, renal ischemia, chronic kidney disease, renal failure,stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine,subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma,chronic obstructive pulmonary disease, high-altitude pulmonary edema,Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonaryedema, pulmonary hypertension, or pulmonary fibrosis. They can also beused for prevention of restenosis after balloon or stent angioplasty,cancer, prostatic hypertrophy, erectile dysfunction, hearing loss,amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock,sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapyand prophylaxis of diabetic complications, complications of vascular orcardiac surgery or after organ transplantation, complications ofcyclosporin treatment, pain, addictions, schizophrenia, Alzheimer'sdisease, anxiety, obsessive-compulsive behavior, epileptic seizures,stress, depression, dementias, neuromuscular disorders,neurodegenerative diseases, as well as other diseases related to adysregulation of urotensin II or urotensin II receptors.

These compositions may be administered in enteral or oral form e.g. astablets, dragees, gelatine capsules, emulsions, solutions orsuspensions, in nasal form like sprays or rectally in form ofsuppositories. These compounds may also be administered inintramuscular, parenteral or intravenous form, e.g. in form ofinjectable solutions.

These pharmaceutical compositions may contain the compounds of formula 1as well as their pharmaceutically acceptable salts in combination withinorganic and/or organic excipients, which are usual in thepharmaceutical industry, like lactose, maize or derivatives thereof,talcum, stearic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquidpolyols etc. may be used. For the preparation of solutions and sirupse.g. water, polyols, saccharose, glucose etc. are used. Injectables areprepared by using e.g. water, polyols, alcohols, glycerin, vegetableoils, lecithin, liposomes etc. Suppositories are prepared by usingnatural or hydrogenated oils, waxes, fatty acids (fats), liquid orhalf-liquid polyols etc.

The compositions may contain in addition preservatives, stabilisationimproving substances, viscosity improving or regulating substances,solubility improving substances, sweeteners, dyes, taste improvingcompounds, salts to change the osmotic pressure, buffer, anti-oxidantsetc.

The compounds of general formula 1 may also be used in combination withone or more other therapeutically useful substances e.g. α- andβ-blockers like phentolamine, phenoxybenzamine, atenolol, propranolol,Uimolol, metoprolol, carteolol, carvedilol, etc.; with vasodilators likehydralazine, minoxidil, diazoxide, flosequinan, etc.; withcalcium-antagonists like diltiazem, nicardipine, nimodipine, verapamil,nifedipine, etc.; with angiotensin converting enzyme-inhibitors likecilazapril, captopril, enalapril, lisinopril etc.; with potassiumchannel activators like pinacidil, chromakalim, etc.; with angiotensinreceptor antagonists like losartan, valsartan, candesartan, irbesartan,eprosartan, telmisartan, and tasosartan, etc.; with diuretics likehydrochlorothiazide, chlorothiazide, acetolamide, bumetamide,furosemide, metolazone, chlortalidone, etc.; with sympatholytics likemethyldopa, clonidine, guanabenz, reserpine, etc.; with endothelinreceptor antagonists like bosentan, tezosentan, darusentan, atrasentan,enrasentan, or sitaxsentan, etc.; with anti-hyperlipidemic agents likelovastatin, pravistatin, fluvastatin, atorvastatin, cerivastatin,simvastatin, etc.; and other therapeutics which serve to treat highblood pressure, vascular disease or other disorders listed above.

The dosage may vary within wide limits but should be adapted to thespecific situation. In general the dosage given daily in oral formshould be between about 3 mg and about 3 g, preferably between about 10mg and about 1 g, especially preferred between 5 mg and 300 mg, peradult with a body weight of about 70 kg. The dosage should beadministered preferably in 1 to 3 doses of equal weight per day. Asusual children should receive lower doses which are adapted to bodyweight and age.

Compounds of the general formula 1 can be prepared using methodsgenerally known in the art, according to the general sequence ofreactions outlined below. For simplicity and clarity reasons sometimesonly a few of the possible synthetic routes that lead to compounds ofgeneral formula 1 are described.

For the synthesis of compounds of general formula 1 general syntheticroutes illustrated in Schemes A through E can be employed. In someinstances one or another of the various groups (R¹ to R⁹, X, Y, Z, n)might be incompatible with the assembly illustrated in Schemes A throughE and so will require the use of protecting groups. The use ofprotecting groups is well known in the art (see for example “ProtectiveGroups in Organic Synthesis, T. W. Greene, Wiley-Interscience, 1981).Particular groups that may require protection are amines (protected asamides or carbamates), alcohols (protected as esters or ethers) andcarboxylic acids (protected as esters). For the purposes of thisdiscussion, it will be assumed that such protecting groups as arenecessary are in place.

1,2,3,4-Tetrahydroisoquinolines and 1,2,3,4-tetrahydrobenz[c]azepines ofgeneral structure I in Schemes A through C are either commerciallyavailable or are prepared in racemic or optically active form by methodswell known in the art. For instance they can be prepared by aring-closing condensation reaction of amides derived from thecorresponding phenylethylamines or phenylpropylamines and theappropriate carboxylic acid under the action of POCl₃ or PCl₅, followedby treatment with a reducing agent such as NaBH₄ (Whaley W M,Govindachari T R “The preparation of 3,4-dihydroisoquinolines andrelated compounds by the Bischler-Napieralski reaction.” Org. React.(1951) 6, 74-106. Finkelstein J, Chiang E, Brossi A “Synthesis of1,2,3,4-tetrahydro-1,1,2,3,3,4,4,-heptamethyl-6,7-dimethoxyisoquinolineand related compounds as potential hypotensive agents.” J. Med. Chem.(1971) 14, 584-588. Ukaji Z, Shimizu Y, Kenmoku Y, Ahmend A, Inomata K“Catalytic asymmetric addition of dialkylzinc to 3,4-dihydroisoquinolineN-oxides utilizing tartaric acid ester as a chiral auxiliary.” Bull.Chem. Soc. Jpn. (2000), 73, 447-452. Zheng W, Nikulin V I, Konkar A A,Vansal S S, Shams G, Feller D R, Miller D D“2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: novelselective beta3-adrenoceptor antagonists.” J Med Chem (1999), 42,2287-2294). Substantially enantiomerically pure1-substituted-2-tetrahydroisoquinoline andI-substituted-2-tetrahydrobenzazepine derivatives are prepared byanalogous methods (Polniaszek R. P. et al., J. Am. Chem. Soc. (1989)111, 4859-4863). The key step of this asymmetric synthesis is astereoselective hydride reduction of a chiral iminium ion obtained byBischler-Napieralski reaction. For the preparation of(R)-1-substituted-2-tetrahydroisoquinoline derivatives the chiralityresident in the substrate is derived from commercially available(R)-(+)-α-phenethylamine.

According to schemes A or B, appropriate 1,2,3,4-tetrahydroisoquinolinesor 1,2,3,4-tetrahydrobenz[c]azepines of general structure I areN-alkylated with suitably protected aminoalkyl halides It orhydroxyalkyl halides III. Removal of the protecting group provides theamines IV or alcohols V. The intermediates IV and V are furtherelaborated to the final compounds of general formula 1 by stepwisetreatment with a carbonylating agent such as carbonyldiimidazole,followed by reaction with a suitable amine VI in the presence of astrong base such as sodium hexamethyldisilazide. This provides the finalcompounds VII and VIII, which correspond to general formula 1, in whichY is NH or O, respectively, and in which n, X, Z and R¹ to R⁶ have thedefinitions given in general formula 1.

An alternative synthetic route to compounds of general formula 1 isillustrated in Scheme C. Thus, carboxylic acids of general structure IXare converted to their corresponding acyl azide, for example by thetreatment with DPPA in a polar aprotic solvent such as DMF. The crudeacyl azide is subjected to thermal rearrangement in an inert solventsuch as toluene, to provide the corresponding isocyanate. Reaction ofthe crude isocyanate with alkyl amines of general structure IV or withalkyl alcohols of general structure V provides the target compounds VIIor VII in which n, X, Y, Z and R¹ to R⁶ have the definitions given ingeneral formula 1.

An alternative synthetic route to compounds of general formula 1 isillustrated in Scheme D. Thus, 1,2,3,4-tetrahydroisoquinolines ofgeneral structure I are N-alkylated with compounds of general structureX (Russell RK et al. “Thiophene Systems. 9 ThienopyrimidinedioneDerivatives as Potential Antihypertensive Agents” J Med Chem 1988, 31,1786-1793) in an aprotic solvent such as THF in the presence of ascavenger base such as NaHCO₃ or di-isopropylethylamine, to provide thetarget compounds XI in which n, X, Y, Z and R¹ to R⁶ have thedefinitions given in general formula 1.

The preparation of the requisite intermediates of general structure X isillustrated in Scheme E, wherein Y, Z and n have the meaning given ingeneral formula 1, and Hal stands for a halogen atom such as chloride.Commercially available or well-known heteroaryl amines of generalstructure VI are reacted with commercially available or well-knownhaloalkyl isocyanates, or haloalkyl chloroformates. Alternatively,compounds of general structure X are prepared by reaction of theisocyanate derived from heteroaryl carboxylic acids IX.

The foregoing general description of the Invention will now be furtherIllustrated by a number of examples which do not at all limit the scopeof the invention.

EXAMPLES

List of Abbreviations

AcOH acetic acid

BSA bovine serum albumin

CDI carbonyldiimidazole

DIPEA diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

DPPA diphenylphosphorylazide

EDC N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide

EDTA ethylenediamine tetra-acetic acid

EtOAc ethyl acetate

Et₂O diethyl ether

Hex hexane

HOBt 1-hydroxybenzotriazole

HPLC high performance liquid chromatography

HV high vacuum conditions

LC-MS liquid chromatography-mass spectroscopy

LAH lithium aluminum hydride

MeOH methanol

min minutes

MHz megahertz

NaHMDS sodium bis(trimethylsilyl)amide

NMR nuclear magnetic resonance

ppm part per million

PBS phosphate-buffered saline

PyBOP (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate

rt room temperature

sat. saturated

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

t_(R) retention time

Reactions are routinely performed under an inert atmosphere such as N₂gas in air dried glassware. Solvents are used as received from thevendor. Evaporations are performed in a rotary evaporator at reducedpressure and a water bath temperature of 50° C. LCMS characterizationsare performed on a Finnigan HP1100 platform using ESl ionization mode,and positive ion detection with a Navigator AQA detector. Analyticalliquid chromatographic separations are performed on a C18 column of4.6×30 mm dimensions and a mobile phase consisting of a 6 minutegradient of 2-95% CH₃CN in water containing 0.50% formic acid at a flowrate of 0.45 mL/min. Retention time (t_(R)) is given in min. TLC isperformed on pre-coated silica gel 60 F₂₅₄ glass-backed plates (Merck).Preparative HPLC is performed on a Varian/Gilson platform using a C18column of 21×60 mm dimensions and a mobile phase consisting of agradient of 2-95% CH₃CN in water containing 0.5% formic acid.

Preparation of Intermediates

Example A

A1. (4-Fluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

2-(3,5-Dimethoxy-phenyl)-ethylamine

To a suspension of LiAlH₄ (1.76 g, 46.4 mmol) in THF (30 mL) is added at0° C. dropwise a solution of 1,3-dimethoxy-5-(2-nitro-vinyl)-benzene(2.43 g, 11.6 mmol; Gairaud C B, Lappin G R, J Org Chem 1953, 18, 1) inTHF (70 mL). The mixture is stirred for 30 min at this temperature andthen at reflux for 4 h. The reaction mixture is quenched by thesubsequent addition of 2 N NaOH (20 mL) and stirred for another 15 minat ambient temperature. The aqueous solution is extracted three timeswith EtOAc. The combined organic layers are dried with anhydrous MgSO₄,filtered and concentrated to give the title compound as a yellow oil.

N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-2-(4-fluoro-phenyl)-acetamide

To a solution of 2-(3,5-dimethoxy-phenyl)-ethylamine (1.01 g, 5.57 mmol)in anhydrous DMF (50 mL) is added 4-fluorophenyl acetic acid (860 mg,5.57 mmol), PyBOP (3.17 g) and N-ethyldiisopropylamine (2.2 mL, 12.8mmol). The mixture is stirred at rt for 14 h. Water (60 mL) is added,and the mixture is extracted with EtOAc (4×60 mL). The combined organicphases are washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by silica gel columnchromatography (EtOAc/Hex, 7:3) to afford the title compound as a yellowoil.

1-(4-Fluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoguinoline

To a stirred solution ofN-[2-(3,5-dimethoxy-phenyl)-ethyl]-2-4-fluoro-phenyl)-acetamide (404 mg,1.27 mmol) in CH₃CN (3 mL) is added POCl₃ (350 μL, 3.82 mmol). Thereaction mixture is stirred at reflux for 30 min. Concentration underreduced pressure gives a residual oil, which is dissolved in MeOH (10mL). To this solution is added portionwise NaBH₄ (340 mg, 8.61 mmol) at0° C. The reaction mixture is allowed to warm to rt and is stirred for14 h. The reaction mixture is poured into water (15 mL) and extractedfour times with CH₂Cl₂. The combined organic layers are dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresidue is purified by flash column chromatography (CH₂Cl₂/MeOH, 9:1) togive the title compound as a brown oil.

Examples A2-A4

The following starting materials are prepared by the method of exampleA1:

A2.1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A3.1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A4.1-(3-Fluoro-4-methoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A5.1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4,-tetrahydro-isoguinoline

N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-3-(4-fluoro-phenyl)-propionamide

2-(3,5-Dimethoxy-phenyl)ethylamine (1.20 g, 6.62 mmol) is dissolved inanhydrous DMF (50 mL), and 3-(4-fluorophenyl) propionic acid (1.113 g,6.62 mmol), PyBOP (3.77 g) and DIPEA (2.61 mL, 15 mmol) are added. Themixture is stirred at rt for 14 h. Water (60 mL) is added, and themixture is extracted with EtOAc (4×60 mL). The combined organic phasesare washed with brine, dried over MgSO₄, filtered and concentrated invacuo. The residue is purified by silica gel column chromatography(EtOAc/Hex, 7:3) to afford the title compound as a yellow oil.

1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4,-tetrahydro-isoguinoline

To a stirred solution ofN-[2-(3,5-dimethoxy-phenyl)-ethyl]-3-(4-fluoro-phenyl)-propionamide(1.25 g, 3.77 mmol) in CH₃CN (12 mL) is added POCl₃ (1.04 mL, 11 mmol).The reaction mixture is stirred at reflux for 30 min. Concentrationunder reduced pressure gives a residual oil, which is dissolved in MeOH(35 mL). To this solution is added portionwise NaBH₄ (1.00 g, 26.4 mmol)at 0° C. and the reaction mixture is allowed to warm to rt and stir for14 h. The mixture is poured into water (40 mL) and extracted with CH₂Cl₂(4×40 mL). The combined organic layers are dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue ispurified by flash column chromatography (CH₂Cl₂/MeOH, 9:1) to give thetitle compound as a brown oil.

Examples A6-A7

The following starting materials are prepared according to the method ofexample A5:

A6.1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A7.1-[2-(3,4-Difluoro-phenylyethyl]-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A8.6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(3-methoxy-phenyl)-propionamide

To a suspension of 3-(3-methoxy-phenyl)-propionic acid (1.19 g, 6.62mmol) and 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (1.33g, 6.95 mmol) in THF (20 mL) is added2-(3,4-dimethoxy-phenyl)-ethylamine (1.20 g, 6.62 mmol). The mixture isstirred at rt for 14 h. The mixture is poured onto H₂O (100 mL) andEtOAc (100 mL). The organic layer is washed successively with saturatedsodium hydrogen carbonate solution, 10% citric acid and saturated sodiumchloride solution. The resulting organic layer is concentrated underreduced pressure to give the title compound.

6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

To a solution ofN-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-3-methoxy-phenyl)-propion-amide(2.21 g, 6.44 mmol) in THF (50 mL) is added POCl₃ (4.91 g, 32.2 mmol)and the resulting solution is refluxed for 1 h. After cooling to rt thesolvent is removed under reduced pressure. The resulting oil is treatedwith methanol (20 mL) and evaporated again. The residue is dissolved inabsolute methanol (40 mL) cooled to 0° C. and NaBH4 (1.21 g, 32.0 mmol)is added in portions. The resulting mixture is stirred at rt for 16 h,and then evaporated. To this residue is added water (150 mL). Theaqueous layer is extracted with CH₂Cl₂ (3×50 mL). The combined extractsare dried over MgSO₄ and concentrated to give the title compound.

Examples A9-A45

The following starting materials are prepared according to the method ofexample A8:

A9.1-[(E)-2-(2,3-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A10.1-[(E)-2-(2,4-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A11.1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A12.1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A13.1-[2-(2,5-Difluoro-phenylyethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A14.1-[2-3,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A15.1-[2-3,4-Dimethoxy-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A16.1-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A17.1-[2-(4-Fluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A18.6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

A19.6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

A20.6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

A21. 6,7-Dimethoxy-1-phenethyl-1,2,3,4-tetrahydro-isoquinoline

A22.1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A23.1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A24.1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A25.1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydro-isoquinoline

A26.1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A27.1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline

A28.1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A29.1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A30. 1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A31. 1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A32. 1-Benzhydryl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A33.1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A34. 1-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A35.6-(3,4-Dimethoxy-benzyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]-isoquinoline

A36. 6,7-Dimethoxy-1-(1-phenyl-propyl)-1,2,3,4-tetrahydro-isoquinoline

A37.6,7-Dimethoxy-1,2,3,4-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

A38.6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

A39. 6,7-Dimethoxy-1-(3-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

A40. 6,7-Dimethoxy-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

A41.6,7-Dimethoxy-1-naphthalen-2-ylmethyl-1,2,3,4-tetrahydro-isoquinoline

A42. 6,7-Dimethoxy-1-phenoxymethyl-1,2,3,4-tetrahydro-isoquinoline

A43.7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline

A44. 1-(3,4-Dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline

A45.1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine

3-(3,4-Dimethoxy-phenyl)-propionamide

To a stirred solution of 3-(3,4-dimethoxy-phenyl)-propionic acid (10.0g, 47.6 mmol) in dry THF (175 mL), under nitrogen, is added TEA (7.3 ml,52.4 mmol). The resulting mixture is cooled to −10° C. before ethylchloroformate (5.0 ml, 52 mmol) is added dropwise. After stirring at−10° C. (20 min), ammonium hydroxide (25% in water, 105 ml) in THF (105mL) is added and the mixture is stirred at −15° C. for 30 min and thenat rt for 1.5 h. The reaction mixture is concentrated in vacuo,extracted three times with CH₂Cl₂ and the combined organic extracts arewashed with saturated aqueous NaHCO₃ and brine. The organic phase isdried over anhydrous MgSO₄, filtered and concentrated to give the titlecompound as a colorless solid.

3-(3,4-Dimethoxy-phenyl)-propylamine

A solution of 3-(3,4-dimethoxy-phenyl)-propionamide (11.1 g, 53.0 mmol)in anhydrous THF (400 ml) is slowly added to a stirred, ice-cooledsuspension of LiAlH₄ (4.02 g, 106 mmol) in anhydrous THF (170 mL). Uponcompletion of the addition, the mixture is stirred at reflux for 2 h.After cooling to 0° C., H₂O (5 mL) and NaOH 1N (5 mL) are added dropwiseto decompose the excess of hydride. The suspension is filtered andevaporated. The residue is partitioned between H₂O (40 mL) and CH₂Cl₂(100 mL). The organic layer is washed with saturated aqueous NaHCO₃ andbrine, dried over anhydrous MgSO₄, and concentrated under reducedpressure to give the title compound as a yellow oil.

2-(3,4-Dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyldropyl]-acetamide

A solution of 3-(3,4-dimethoxy-phenyl)-propylamine (12.5 g, 64.1 mmol)and TEA (10 mL, 71.8 mmol) in anhydrous THF (70 mL) is cooled to 0° C.and (3,4-dimethoxy-phenyl)-acetyl chloride (13.8 g, 64.1 mmol) in THF(28 mL) is added dropwise. After stirring at rt for 13 h under nitrogen,a saturated aqueous NaHCO₃ solution is added and the reaction mixture isextracted three times with EtOAc. The organic phase is dried overanhydrous MgSO₄, filtered and the solvent evaporated. The residue iswashed with toluene and dried to give the title as a beige solid.

1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine

A mixture of2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-acetamide(6.16 g, 16.5 mmol) and POCl₃ (4.95 mL, 54.1 mmol) in anhydrousacetonitrile (185 mL) is stirred at reflux for 4 h under nitrogen. Aftercooling, the reaction mixture is evaporated and the residue is dissolvedin MeOH (125 mL). The solution is cooled to 0° C. and NaBH₄ (4.31 g, 114mmol) is added portionwise. After stirring at 0° C. for 2 h undernitrogen, the reaction mixture is poured into H₂O and extracted threetimes with CH₂Cl₂. The combined organic extracts are washed with brine,dried over anhydrous MgSO₄, filtered and concentrated to give a crudeoil. Flash chromatography (CH₂Cl₂/MeOH: 9/1) yields the title compoundas a yellow oil.

A46.1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoguinoline

3-(2,3-Difluoro-phenyl)-propionic Acid

To a suspension of 2,3-difluoro-cinnamic acid (2.94 g, 16 mmol) inethanol (100 mL) is added Pd (10% on carbon, 50 mg) and the mixture istreated with hydrogen (7.5 bar) for 15 h. The suspension is filteredthrough celite and the solvent evaporated to provide the title compound.

1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

The compound is prepared from 3-(2,3-difluoro-phenyl)-propionic acid and2-(3,4-dimethoxy-phenyl)-ethylamine according to the method of exampleA8.

Example A47

The following starting material is prepared according to the method ofexample A46:

A47.1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A48.1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoguinoline-7-carboxylicacid dime thylamide.

2-(4-Benzyloxy-3-methoxy-phenyl)-vinylamine

A stirred suspension of LAH (8.0 g, 0.21 mol) in THF (300 mL) is cooledin an ice bath and a solution of 4-benzyloxy-3-methoxynitrostyrene (15.0g, 52.6 mmol) in THF (300 mL) is added dropwise. The green reactionmixture is allowed to warm to room temperature over 0.5 h, and is thenrefluxed for 4 h. The grey reaction mixture is treated successively withwater (8 mL), 15% aqueous NaOH (8 mL), and water (24 mL). The resultinggray suspension is stirred at 50° C. for 20 min. The resulting yellowsuspension is filtered, and the residue is washed with EtOAc. Thecombined filtrates are evaporated to provide the title compound asyellow oil which is used without further purification.

N-[2-(4-Benzyloxy-3-methoxy-phenyl)-vinyl]-2-(3,4-dichloro-phenyl)-acetamide

A mixture of 3,4-dichlorophenyl acetic acid (10.6 g, 51.7 mmol) and2-4-benzyloxy-3-methoxy-phenyl)-vinylamine (12.1 g, 47 mmol) in toluene(100 mL) is heated at reflux in a Dean-Stark apparatus for 17 h. Thereaction is allowed to cool to rt. Filtration yields the title compoundas yellow crystals. The filtrate is heated again at reflux in aDean-Stark apparatus for 16 h, and then allowed to cool to rt.Filtration provides a second portion of the title compound as yellowcrystals. The two batches are combined and used without furtherpurification.

7-Benzyloxy-1-(3,4-dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline

To a suspension ofN-[2-(4-benzyloxy-3-methoxy-phenyl)-vinyl]-2-(3,4-dichloro-phenyl)-acetamide(13.3 g, 30 mmol) in CH₃CN (100 mL) at rt is added dropwisephosphoroxychloride (8.1 mL, 13.5 g, 88 mmol). The resulting whitesuspension is heated to reflux, and the resulting yellow solution isheated at reflux for 3 h. The dark yellow solution is allowed to cooland is evaporated to a yellow oil. The oil is taken up in MeOH (100 mL)and evaporated to yield an orange solid. The material is redissolved inMeOH (100 mL) and the solution is cooled to 0° C. NaBH₄ (3.61 g, 95mmol) is added in portions with gas evolution and a strong exotherm. Theresulting white suspension is stirred at rt for 16 h. The reactionmixture is partitioned between EtOAc (200 mL) and water (200 mL), andthe aqueous phase is extracted with EtOAc (3×200 mL). The combinedorganic phase is washed with water and brine, and evaporated to providethe title compound as a faint yellow oil which is used without furtherpurification.

1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-ol

To a solution of7-benzyloxy-1-(3,4-dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline(14.1 g, 30 mmol) in MeOH (150 mL) and 1,2-dichlorobenzene (30 mL) isadded 50% Pd on charcoal (500 mg). The reaction vessel is flushed withnitrogen and then with hydrogen at atmospheric pressure. After stirringat rt for 16 h, the reaction mixture is filtered through Hyflo, andevaporated to yield to the title compound as a beige solid which is usedwithout further purification.

1-(3,4-Dichloro-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoguinoline-2-carboxylicAcid Tert-butyl Ester

To a solution of1-(3,4-dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-ol(9.6 g, 28 mmol) in isopropanol (30 mL) is added dropwise 1 M aqueousNaOH (30 mL) and di-tert-butyl-dicarbonate (6.7 g, 30.8 mmol). Theresulting brown solution is stirred at rt for 30 min, and the resultingyellow solution is partioned between EtOAc (50 mL) and water (50 mL).The organic phase is washed successively with water and with brine, andis evaporated to provide the title compound as yellow oil, which is usedwithout further purification.

1-(3,4-Dichloro-benzyl)-6-methoxy-7-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylicAcid Tert-butyl Ester

To a solution of1-(3,4-dichloro-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (12 g, 27 mmol) in CH₂Cl₂ (100 mL) is added Et₃N(3.8 mL, 27 mmol). The reaction mixture is cooled to 0° C. andtrifluoromethanesulfonic anhydride (4.45 mL, 27 mmol) is added. Theresulting yellow solution is stirred at rt 30 min, and is poured ontoaqueous saturated NaHCO₃ (100 mL). The aqueous phase is extracted withCH₂Cl₂ (2×100 mL), and the combined organic phases are dried (MgSO4),filtered and evaporated to provide the title compound as yellow oil.Purification is achieved by crystallization from MeOH. The evaporatedmother liquor furnishes additional material upon silica gelchromatography (heptane:Et2O, 9:1).

7-Cyano-1-(3,4-dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoguinoline-2-carboxylicAcid Tert-butyl Ester

A solution of1-(3,4-dichloro-benzyl)-6-methoxy-7-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (10 g, 17 mmol) in DMF (15 mL) standing overfreshly dried 4 A molecular sieves is deoxygenated by bubbling withargon for 20 min. This solution is added to a deoxygenated suspension ofzinc cyanide (4.6 g, 34 mmol) in DMF (15 mL) under argon. The resultinglight brown suspension is placed in a 120° C. oil bath.Tetrakis-(triphenylphosphine)-palladium (1.0 g) is added, and the brownreaction mixture is stirred at 120° C. for 2 h. The reaction mixture iscooled to rt, and partitioned between EtOAc and saturated aqueousNaHCO₃. The mixture is filtered through Hyflo. The aqueous phase isextracted with EtOAc (3×40 mL). The combined organic phases areextracted with brine, dried over MgSO₄, filtered, and evaporated. Theresulting yellow oil partially solidifies. The mixture is filtered andwashed with Et₂O to provide the title compound as white crystals.Evaporation of the filtrate and silica gel chromatography(EtOAc:heptane, 1:4) provides additional title compound as whitecrystals.

1-(3,4-Dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2,7-dicarboxylicAcid 2-tert-butyl Ester

To a solution of7-cyano-1-(3,4-dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (3.60 g, 8.06 mmol) in benzyl alcohol (10 mL) isadded KOH (3.00 g), and the reaction mixture is stirred at 160° C. for0.5 h. The reaction mixture is allowed to cool to rt and is acidifiedwith 2 M aqueous HCl. The reaction mixture is partitioned with EtOAc(3×20 mL). The combined organic phases are washed with brine, dried overMgSO₄, filtered, and evaporated to yield a yellow oil. Chromatographyover silica gel with CH₂Cl₂:MeOH 19:1 and then with MeOH provides thetitle compound as yellow solid.

1-(3,4-Dichloro-benzyl)-7-dimethylcarbamoyl-6-methoxy-3,4-dihydro-1H-isoguinoline-2-carboxylicAcid Tert-butyl Ester

To a solution of1-(3,4-dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2,7-dicarboxylicacid 2-tert-butyl ester (1.0 g, 2.1 mmol) in CH₂Cl₂ (10 mL) is addeddimethylamine hydrochloride (0.35 g, 4.3 mmol), HOBt (65 mg, 0.43 mmo),DMAP (52 mg, 0.43 mmol), and EDC hydrochloride (493 mg, 2.6 mmol). Thereaction mixture was stirred at rt for 16 h. The fine yellow suspensionis diluted with CH₂Cl₂ (10 mL), and is washed with 1 M aqueous HCl andsaturated aqueous NaHCO₃. The organic phase is dried over MgSO₄,filtered and evaporated to give the title compound.

1-(3,4-Dichloro-benzyl)6-methoxy-1,2,3,4-tetrahydro-isoguinoline-7-carboxylic AcidDimethylamide

A solution of1-(3,4-dichloro-benzyl)-7-dimethylcarbamoyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.0 g, 2.0 mmol) in 4 M HCl in dioxane is stirredat 0° C. for 1 h. The reaction mixture is evaporated to provide thetitle compound as a white solid.

Examples A49-A50

The following starting materials are prepared according to the method ofexample A48:

A49.1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carboxylicacid methylamide

A50.1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carboxylicacid propylamide

Examples A51-A52

Enantiomerically pure starting materials are prepared according to themethod of Polniaszek R. P. et al., J. Am. Chem. Soc. (1989) 111,4859-4863.

A51.(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

A52.(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

Preparation of Intermediates

Example B

B1. (2-Bromo-ethyl)-carbamic Acid Tert-butyl Ester

To 1 N aqueous NaOH (200 mL) is added to MeOH (400 mL) and the resultingsolution is cooled to 20° C. 2-Bromoethylamine hydrobromide (25.0 g, 122mmol) is added in a single portion, followed di-tert-butyl dicarbonate(26.6 g, 122 mmol). The reaction mixture is stirred for 2.5 h. The MeOHis removed on a rotary evaporator, and the aqueous suspension isextracted with CH₂Cl₂ (2×175 mL). The combined organic phases areextracted with 5% aqueous citric acid (300 mL), dried over MgSO₄,filtered, and evaporated to provide the title compound.

B2. (3-Chloro-propyl)-carbamic Acid Tert-butyl Ester

This material is prepared analogously to example B1 from3-chloropropylamine.

Preparation of Intermediates

Example C

C1. 4-Amino-2-methylquinoline.

This material is commercially available.

C2. 4-Amino-pyridine.

This material is commercially available.

C3. 4-Amino-quinoline.

Prepared from commercial 4-nitroquinoline N-oxide according to themethod described in Shinkai H et al., “4-Aminoquinolines: NovelNociceptin Antagonists with Analgesic Activity”, J. Med. Chem. (2000)43, 4667-4677.

C4. 4-Amino-6,7,8,9-tetrahydro-quinoline.

6,7,8,9-Tetrahydro-quinoline-N-oxide

A solution of 5,6,7,8-tetrahydroquinoline (2.66 mL, 20 mmol) in THF (125mL) is cooled to 0° C. and a solution of m-chloroperbenzoic acid (3.8 g,22 mmol) in THF (25 mL) is added. After 0.5 h the mixture is evaporatedin vacuo and redissolved in CH₂Cl₂ (75 mL). The solution is washed withNaOH (1 M, 20 mL) and citric acid (10%, 20 mL), dried and evaporated toprovide the title compound.

4-Nitro-6,7,8,9-tetrahydro-quinoline-N-oxide

5,6,7,8-Tetrahydroquinoline-N-oxide (298 mg, 2 mmol) is treated with acooled mixture of HNO₃ (100%, 0.5 mL) and H₂SO₄ (98%, 0.7 mL). Themixture is heated to 80° C. for 2 h, poured into ice (100 g) andextracted with CH₂Cl₂ (30 mL). The organic phase is dreid and evaporatedto provide the title compound.

4-Amino-6,7,8,9-tetrahydro-quinoline.

Prepared from 4-nitro-6,7,8,9-tetrahydro-quinoline-N-oxide according tothe method of example C3.

C5. 4-Amino-7-methyl-[1,8]-naphthyridine.

Prepared according to the method described in Barlin G B, Tan W L,“Potential Antimalarials. I 1,8-naphthyridines”, Aust J Chem (1984) 37,1065-1073. Radivov R, Haimova M, Simova E “Synthesis of4-Amino-3-Pyridiyl and 4-Amino-5-Pyrimidyl Aryl Ketones and RelatedCompounds via an ortho-Lithiation Reaction”, Synthesis (1986), 886-891.

C6. Quinoline-4-carboxylic Acid.

This material is commercially available.

C7. 2-Methyl-quinoline-4-carboxylic Acid.

This material is prepared by reaction of isatin with acetone accordingto the method described in Brasyunas V B et al., “Synthesis ofQuinoline-4-carboxylic acid and its derivatives”, Chem. Heterocycl.Compd. (engi. Transl.) (1988) 670-673.

C8. 2-(Benzyl-methyl-amino)-isonicotinic Acid.

A mixture of 2-chloro-pyridine-4-carboxylic acid (300 mg, 1.9 mmol),benzylmethylamine (230 mg, 1.9 mmol) and triethylamine (192 mg, 1.9mmol) is heated to 120° C. for 12 h. The residue is dissolved in CH₂Cl₂(30 mL) and extracted with 1M NaOH (3×5 mL). The aqueous phase isadjusted to pH 2 and extracted with EtOAc (6×5 mL). The organic phasesare combined, dried (MgSO₄), and evaporated to provide the titlecompound.

C9. 2-(Benzyl-methyl-amino)-6-methyl-isonicotinic Acid.

This material is prepared by reaction of2-chloro-6-methyl-pyridine-4-carboxylic acid with benzylmethylamineanalogously to example C8.

C10. 2-(Methyl-phenyl-amino)-isonicotinic Acid.

This material is prepared by reaction of 2-chloro-pyridine-4-carboxylicacid with N-methylaniline analogously to example C8.

C11. 2-Pyrrolidin-1-yl-isonicotinic Acid.

This material is prepared by reaction of 2-chloro-pyridine-4-carboxylicacid with pyrrolidine analogously to example C8.

Preparation of Intermediates

Example D

D1. 1-(2-Chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea.

To a solution of 4-amino-2-methylquinoline (example C1, 12.6 g, 80 mmol)in THF (480 mL) is added 2-chloroethylisocyanate (10.2 mL, 120 mmol) atrt. The reaction mixture is stirred for 40 h at rt. MeOH (100 mL) isadded, and stirring is continued an additional hour. The reactionmixture is evaporated and the residue is taken up in CH₂Cl₂. The organicphase is shaken with 1 N HCl (250 mL), and the resulting precipitate iscollected by filtration. The solid is washed with CH₂Cl₂ (100 mL),saturated NaHCO₃ (2×100 mL), and with water (4×100 mL). The resultingsolid is dried under HV at rt for 14 h to provide the title compound.

D2. 1-(3-Chloro-propyl)-3-(2-methyl-quinolin-4-yl)-urea.

Analogously to method D1 the title compound is prepared from4-amino-2-methylquinoline (example C1) and 3-chloropropylisocyanate.

D3. 1-(2-Chloro-ethyl)-3-(quinolin-4-yl)-urea.

Analogously to method D1 the title compound is prepared from4-amino-2-quinoline (example C3) and 2-chloroethylisocyanate.

D4. 1-(3-Chloro-propyl)-3-(quinolin-yl)-urea.

Analogously to method D1 the title compound is prepared from4-amino-2-quinoline (example C3) and 3-chloropropylisocyanate.

D5. 1-(2-Chloro-ethyl)-3-(pyridin-4-yl)-urea.

Analogously to method D1 the title compound is prepared from4-amino-pyridine (example C2) and 2-chloroethylisocyanate.

D6. 1-(2-Chloro-ethyl)-3-(7-methyl-[1,8]-naphthyridin-4-yl)-urea.

Analogously to method D1 the title compound is prepared from4-amino-7-methyl-[1,8]-naphthyridine (example C5) and2-chloroethylisocyanate.

Preparation of Final Products

Example 1

1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea.

To a solution of1-(4-fluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline(example A1, 50 mg, 0.16 mmol) in anhydrous THF (2.5 mL) is added1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (example D1, 43.8 mg,0.16 mmol), TEA (34.6 μL, 0.25 mmol) and Nal (2.5 mg, 0.017 mmol). Themixture is stirred at 75° C. for five days in a sealed flask. Thereaction mixture is evaporated, and the residue is purified bypreparative HPLC to provide the title compound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=0.93 min, m/z=529.3 (M+1)

Examples 2-6

The additional examples set out in the following table are preparedstarting from examples A1 to A4 and examples D1 or D3 using the methodof example 1.

Exam- ple [M + No Example t_(R) H]⁺ 2 1-{2-[1-(3,4-Difluoro- 0.97 547.30benzyl)-6,8-dimethoxy-3,4- dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 31-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8- 1.05 559.70dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]- ethyl}-3-(2-methyl-quinolin-4-yl)-urea 4 1-{2-[1-(3,4-Difluoro-benzyl)-6,8- 0.80 533.30dimethoxy-3,4-dihydro-1H- isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea5 1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8 1.13 545.24-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]- ethyl}-3-quinolin-4-yl-urea6 1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4- 0.78 515.30dihydro-1H-isoquinolin-2-yl]-ethyl}-3- quinolin-4-yl-urea

Example 7

1-{2-(4-Fluoro-phenyl)ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinoline-4-yl)-urea.

1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4,-tetrahydro-isoquinoline(example A5, 100 mg, 0.317 mmol) is dissolved in anhydrous THF (3.0 mL),1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (example D1, 83.6 mg,0.317 mmol), TEA (66.2 μL, 0.475 mmol) and NaI (4.8 mg, 0.032 mmol) areadded. The mixture is stirred at 75° C. for five days in a sealed flask.The reaction mixture is evaporated, and the residue is purified bypreparative HPLC to provide the title compound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=1.11 min, m/z=543.5 (M+1)

Examples 8-9

The additional examples set out in the following table are preparedstarting from examples A5 to A7 and examples D1 or D3 using the methodof example 7.

Exam- ple No Example t_(R) [M + H]⁺ 81-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8- 1.16 561.34dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 91-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8- 1.15 547.32dimethoxy-3,4-dihydro-1H-isoquinolin-2- y}-ethyl)-3-quinolin-4-yl-urea10 1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8- 1.16 561.33dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 111-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8- 1.16 547.31dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl}-ethyl)-3-quinolin-4-yl-urea12 1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,8- 1.15 529.30dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl}-ethyl)-3-quinolin-4-yl-urea

Example 13

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea.

To a solution of1-(4-fluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline(example A31, 0.16 g, 0.50 mmol) in THF (2 mL) is added1-(2-chloroethyl)-3-(2-methylquinolin-yl)-urea (example D1, 0.18 g, 0.60mmol), solid NaHCO₃ (50 mg, 0.6 mmol) and NaI (15 mg, 0.1 mmol). Themixture is stirred at 70° C. in a sealed flask for 5 days. The mixtureis evaporated, and the residue is purified by preparative HPLC toprovide the title compound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=1.10 min, m/z=529.19 (M+1)

Examples 14-105

The additional examples set out in the following table are preparedstarting from examples A1 to A52 and examples D1 to D5 using the methodof example 13.

Example No Example t_(R) [M + H]⁺ 141-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy- 1.01 585.191,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 151-(2-{1-[(E)-2-(2,4-Difluoro-phenyl)-vinyl]-6,7- 1.13 559.31dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 161-(2-{1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7- 1.13 559.30dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 171-(2-{1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.33dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 181-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.34dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 191-(2-{1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7- 1.18 661.30dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 201-(2-{1-[2-(2,5-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.32dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 211-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.32dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 221-(2-{1-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6,7- 1.09 585.37dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 231-(2-{1-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7- 1.19 661.30dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 241-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,7-dimethoxy- 1.14 543.323,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea25 1-(2-{6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]- 1.13 555.363,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea26 1-(2-{6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]- 1.13 555.363,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea27 1-(2-{6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-ethyl]- 1.13 555.373,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea28 1-(2-{6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)- 1.17 593.35ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 291-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.11 525.22isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)- urea 301-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.07 461.12isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 311-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.11 511.07isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 321-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.11 539.26isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)- urea 331-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.10 525.18isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea 341-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy- 1.14 555.213,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl- quinolin-4-yl)-urea35 1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy- 0.99 491.073,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl- urea 361-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy- 1.06 541.073,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4- yl-urea 371-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)- 1.03 387.12ethyl]-3-pyridin-4-yl-urea 381-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)- 1.10 437.08ethyl]-3-quinolin-4-yl-urea 391-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.09 511.17isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)- urea 401-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 0.98 447.10isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 411-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.07 497.08isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 421-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H- 1.06 417.09isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 431-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H- 1.11 467.12isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 441-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4- 1.10 497.10dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl- urea 451-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4- 1.12 547.14dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl- urea 461-[2-(6,7-Dimethoxy-1-phenoxymethyl-3,4-dihydro- 0.98 463.091H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 471-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.08 525.25isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)- urea 481-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.04 511.17isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea 491-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.04 507.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 501-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.10 557.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 511-{2-[1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-3,4- 1.12 579.26dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 521-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4- 1.04 483.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 531-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4- 1.10 533.04dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 541-{2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4- 1.10 587.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 551-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 0.94 507.16dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 561-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.01 557.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 571-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 0.83 561.30dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea 581-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 571.21dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 591-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.08 507.16dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 601-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 557.18dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 611-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4- 1.02 477.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 621-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4- 1.08 527.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 631-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy- 1.11 559.333,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea64 1-{2-[1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7- 1.15 597.33dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 651-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4- 1.09 481.04dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 661-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4- 1.11 531.08dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 671-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro- 1.01 465.111H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 681-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro- 1.09 515.061H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 691-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4- 1.00 537.17dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 701-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4- 1.08 587.09dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 711-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4- 1.12 601.29dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 721-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4- 0.96 537.09dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 731-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4- 1.03 587.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 741-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4- 1.00 477.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 751-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4- 1.08 527.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 761-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4- 0.99 477.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 771-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4- 1.07 527.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 781-{3-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4- 1.09 547.18dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl- urea 791-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.03 585.20dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl- quinolin-4-yl)-urea 801-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.01 571.19dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl- urea 811-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 585.21dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl- quinolin-4-yl)-urea 821-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 571.21dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl- urea 831-{3-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro- 1.07 529.221H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea 841-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H- 0.99 491.09[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-pyridin-4- yl-urea 851-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H- 1.07 541.08[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-quinolin- 4-yl-urea 861-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro- 1.00 505.076H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3- pyridin-4-yl-urea 871-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro- 1.06 555.086H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3- quinolin-4-yl-urea 881-[2-(1-Benzhydryl-5,8-dimethoxy-3,4-dihydro-1H- 1.14 573.11isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 891-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H- 1.10 523.07isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 901-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H- 1.12 573.08isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 911-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H- 1.09 447.15isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 921-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H- 1.13 497.09isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 931-{2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4- 1.11 557.08dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 941-{2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4- 1.14 557.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 951-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4- 1.08 475.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 961-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4- 1.11 525.09dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 971-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4- 1.29 585.29dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3- quinolin-4-yl-urea98 1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy- 1.05 571.353,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea99 1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy- 1.01 557.143,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4- yl-urea 1001-{2-[(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4- 0.77 529.08dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 1011-{2-[7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6- 0.82 647.1methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1021-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4- 0.77 541.13dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 1031-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2- 0.78 606.13methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid methylamide 1041-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2- 0.82 634.04methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid propylamide 1051-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2- 0.78 620.00methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid dimethylamide

Example 106

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(7-methyl-[1,8]naphthyridin-4-yl)-urea

106.1.{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicAcid Tert-butyl Ester

To a solution of1-(4-fluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline(example A31, 1.05 g, 3.5 mmol) in THF (40 mL) is added(2-bromo-ethyl)-carbamic acid tert-butyl ester (example B1, 0.94 g, 4.2mmol) and DIPEA. The reaction mixture is stirred at 70° C. in a sealedflask for 5 days. After cooling to rt, the reaction mixture isevaporated to dryness, and the residue is purified by preparative HPLCto provide the title compound.

106.2.1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethy}-3-(7-methyl-[1,8]naphthyridin-4-yl)-urea

To a stirred solution of{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in glacial AcOH(1 mL) is added conc. HCl (0.1 mL). After 5 min, the reaction mixture ispartitioned with CHCl₃ (20 mL) and 1 N NaOH (15 mL). The organic phaseis evaporated. The residue is taken up in DMSO (2 mL) and treated withCDI (0.2 g, 0.6 mmol, 1.2 eq). The reaction mixture is stirred at rt for3 h, and then 4-amino-7-methyl-[1,8]-naphthyridine (example C5, 0.19 g,0.6 mmol) is added. To the resulting solution is added in a singleportion NaHMDS (2 M in THF, 1.25 mL, 2.5 mmol). The reaction mixture isstirred at rt for 30 min, then H₂O (0.4 mL) is added. The reactionmixture is evaporated and the residue purified by preparative HPLC toprovide the title compound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=0.92 min, m/z=530.3 (M+1)

Example 107

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea

To a stirred solution of{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in glacial AcOH(1 mL) is added conc. HCl (0.1 mL). After 5 min, the reaction mixture ispartitioned between CHCl₃ (20 mL) and 1 N NaOH (15 mL). The organicphase is evaporated. The residue is taken up in DMSO (2 mL) and treatedwith CDI (0.2 g, 0.6 mmol, 1.2 eq). The reaction mixture is stirred atrt for 3 h, and then 4-amino-5,6,7,8-tetrahydroquinoline (example C4,0.19 g, 0.6 mmol) is added. To the resulting solution is added in asingle portion NaHMDS (2 M in THF, 1.25 mL, 2.5 mmol). The reactionmixture is stirred at rt for 30 min, then H₂O (0.4 mL) is added. Thereaction mixture is evaporated and the residue purified by preparativeHPLC to provide the title compound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=0.92 min, m/z=519.3 (M+1)

Example 108

1-[2-(Benzyl-methyl-amino)-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea

108.1 Benzyl-(4-isocyanato-pyridin-2-yl)-methyl-amine

To a solution of 2-(benzyl-methyl-amino)-isonicotinic acid (example C8,780 mg, 3.2 mmol) in DMF (10 mL) at 0° C. is added triethylamine (360mg, 3.5 mmol). After 5 minutes DPPA (975 mg, 3.5 mmol) is added, andstirring is continued for 2 h at 0° C. and 12 h at 20° C. The reactionis quenched with ice (10 g) and extracted with Et₂O (6×30 mL). Thecombined organic phases are washed successively with saturated NaHCO₃(2×15 mL) and water (2×10 mL), and are evaporated without heating invacuo. The residue is dissolved in dry toluene (16 mL) and heated toreflux for 2 h. The resulting solution is carried forward withoutfurther isolation of the title compound.

108.21-[2-(Benzyl-methyl-amino)-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea

To a stirred solution of{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in CH₂Cl₂ (1 mL)is added TFA (1 mL). After 2 h, the reaction mixture evaporated andpartitioned between CH₂Cl₂ (20 mL) and 1 N NaOH (15 mL). The organicphase is dried (MgSO₄) and evaporated. The residue is dissolved inCH₂Cl₂ (2 mL) and added to a freshly prepared solution ofbenzyl-(4-isocyanato-pyridin-2-ylmethyl-amine (example 108.1, 95.7 mg,0.40 mmol) in toluene (2 mL). The mixture is stirred for 15 h at 20° C.Evaporation of the solvent and purification by HPLC provides the titlecompound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=0.73 min, m/z=584.3 (M+1)

Examples 109-111

The additional examples set out in the following table are preparedstarting from example 106.1 and examples C9 to C11 using the method ofexample 108.

Example No Example t_(R) [M + H]⁺ 109 1-[2-(Benzyl-methyl-amino)-6- 0.76598.43 methyl-pyridin-4-yl]-3- {2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl]-ethyl}-urea 1101-{2-[1-(4-Fluoro-benzyl)-6,7- 0.80 570.10 dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-[2- (methyl-phenyl-amino)-pyridin-4-yl]-urea 111 1-{2-[1-(4-Fluoro-benzyl)- 0.77 534.096,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl]-ethyl}-3-(2-pyrrolidin-1-yl- pyridin-4-yl)-urea

Example 112

1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methylamino-1-yl-pyridin-4-yl)-urea

To a mixture of1-[2-(benzyl-methyl-amino)pyridin-4-yl]-3{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea(example 108, 0.12 g, 0.2 mmol) and Pd (10% on carbon, 20 mg) in MeOH(10 mL) is added HCl (1N, 0.2 mL). A stream of hydrogen is passedthrough the solution for 0.5 h and the solution is stirred under anatmosphere of hydrogen for 15 h. The solution is filtered and evaporatedto provide the title compound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=0.77 min, m/z=534.09 (M+1)

Example 113

(Quinolin-4-yl)-carbamic acid2-(6.7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethylEster

113.1.2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanol

A solution of 6,7-dimethoxy-1-phenethyl-1,2,3,4-tetrahydro-isoquinoline(example A21, 59.5 mg, 0.2 mmol) and 2-bromoethanol (28.3 μL, 0.4 mmol)in tetrahydropyran (3 mL) is treated with DIPEA (68 μL, 0.4 mmol), andthe reaction mixture is heated at 90° C. in a sealed flask for 5 days.The reaction is mixture evaporated to dryness, and the residue ispurified by preparative HPLC, to provide the title compound.

113.2. (Quinolin-4-yl)-carbamic Acid2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethylEster

To a solution of2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanol(example 113.1, 29.7 mg, 0.087 mmol) in THF (1 mL) is added CDI (28.2mg, 0.174 mmol, 2.0 eq). The reaction mixture is stirred at rt for 3 h,and then 4-amino-quinoline (example C3, 14 mg, 0.1 mmol) is added. Tothe resulting solution is added in a single portion NaHMDS (2 M in THF,218 μL, 0.44 mmol). The reaction mixture is stirred at rt for 30 min,then H₂O/AcOH (9:1, 0.4 mL) is added. The reaction mixture is evaporatedand the residue purified by preparative HPLC to provide the titlecompound.

LC-MS (MeCN/H₂O, 1:1) t_(R)=1.17 min, m/z=512.19 (M+1)

Examples 114-120

The additional examples set out in the following table are preparedstarting from examples A1 to A52 and examples C1 to C3 using the methodof example 113.

Example No Example t_(R) [M + H]⁺ 114 Quinolin-4-yl-carbamic acid2-(1-benzyl-6,7- 1.09 498.19dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl ester 115Quinolin-4-yl-carbamic acid 2-[1-(4-fluoro-benzyl)- 1.12 516.166,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl ester 116Quinolin-4-yl-carbamic acid 3-(1-benzyl-6,7- 1.05 512.15dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester 117Quinolin-4-yl-carbamic acid 3-(6,7-dimethoxy-1- 1.10 526.19phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester 118Quinolin-4-yl-carbamic acid 3-[1-(3,4-difluoro- 1.10 548.18benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl]-propyl ester 119Quinolin-4-yl-carbamic acid 3-[1-(3,4-dimethoxy- 1.10 572.25benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl]-propyl ester 120Quinolin-4-yl-carbamic acid 3-[1-(4-fluoro-benzyl)- 1.08 530.126,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]- propyl ester

Example 121

In Vitro Biological Characterization

The inhibitory activity of the compounds of general formula 1 on theactions of urotensin II can be demonstrated using the test proceduresdescribed hereinafter:

1) Inhibition of Human [125I]-urotensin II Binding to a RhabdomyosarcomaCell Line

Whole cell binding of human [¹²⁵I]-urotensin II is performed usinghuman-derived TE-671 rhabdomyosarcoma cells (Deutsche Sammlung vonMikroorganismen und Zellkulturen, cell line #ACC-263), by methodsadapted from a whole cell endothelin binding assay (Breu V et al., Invitro characterization of Ro-46-2005, a novel synthetic non-peptideantagonist of ET_(A) and ET_(B) receptors. FEBS Lett. 1993, 334,210-214).

The assay is performed in 250 μL Dubecco's modified eagle medium, pH 7.4(GIBCO BRL, CatNo 31885-023), including 25 mM HEPES (Fluka, CatNo05473), 1.0% DMSO (Fluka, CatNo 41644) and 0.5% (w/v) BSA Fraction V(Fluka, CatNo 05473) in polypropylene microtiter plates (Nunc, CatNo442587). 300,000 suspended cells are incubated with gentle shaking for 4h at 20° C. with 20 pM human [¹²⁵I]Urotensin II (Anawa Trading SA,Wangen, Switzerland, 2130 Ci/mmol) and increasing concentrations ofunlabeled antagonist. Minimum and maximum binding are derived fromsamples with and without 100 nM unlabelled U-II, respectively. After the4 h incubation period, the cells are filtered onto GF/C filter plates(Packard, CatNo 6005174). The filter plates are dried, and then 50 μLscintillation cocktail (Packard, MicroScint 20, CatNo 6013621) is addedto each well. The filter plates are counted in a microplate counter(Packard Bioscience, TopCount NXT).

All test compounds are dissolved and diluted in 100% DMSO. A ten-folddilution into assay buffer is performed prior to addition to the assay.The final concentration of DMSO in the assay is 1.0/, which is found notto interfere with the binding. IC50 values are defined as theconcentration of antagonist inhibiting 50% of the specific binding of[¹²⁵I]human U-II. Specific binding is the difference between maximumbinding and minimum binding, as described above. An IC50 value of 0.206nM is found for unlabeled human U-II. The compounds of the invention arefound to have IC50 values ranging from 1 to 10000 nM in this assay.Specific examples have IC50's given in the following table.

Example IC50 [nM] 20 67 22 63 29 125 58 550

2) Inhibition of Human Urotensin II-Induced Contractions of Isolated RatAortic Arch

Adult Wistar rats are anesthetized (CO₂ inhalation) and exsanguinated.The aortic arch is excised, dissected and cut in 3 rings of 3 mm, ring#1 being the more proximal and ring #3 being the more distal. Each ringis suspended in a 10 mL isolated organ bath filled with Krebs-Henseleitsolution (in mM; NaCl 115, KCl 4.7, MgSO₄ 1.2, KH₂PO₄ 1.5, NaHCO₃ 25,CaCl₂ 2.5, glucose 10; pH 7.4) kept at 37° C. and gassed with 95% O₂ and5% CO₂. The rings are connected to force transducers and isometrictension is recorded (EMKA Technologies SA, Paris, France). The rings arestretched to a resting tension of 3 g. Cumulative doses of humanurotensin II (10⁻¹¹ M to 10⁻⁶ M) are added after a 20 min incubationwith the test compound or its vehicle (DMSO, 10 μL). An EC50 value of1.09±0.1 nM is found for unlabeled human U-II. The functional inhibitorypotency of the test compound is assessed by calculating the pD₂′according to the formula: pD₂′=Log (CR-1)-Log [B], where CR is the ratioof the maximal effect without/with antagonist and [B] the concentrationof the antagonist. Specific examples have pD2′ values given in thefollowing table:

Example pD2′ 29 5.23 93 5.45

What is claimed is:
 1. A compound of the general formula 1,

wherein X represents —CH₂—, —CH₂CH₂—, —C(CH₃)₂—; Y represents oxygen,NH; n represents the numbers 1 or 2; Z represents quinolin-4-yl whichmay be mono-substituted with lower alkyl in the positions 2, 6, or 8, ordi-substituted with lower alkyl in the positions 2,6 or 2,8;[1,8]naphthyridin-4-yl which may be substituted in position 7 with loweralkyl; pyridin-4-yl which may be substituted in position 2 with R⁷R⁸N—and additionally in position 6 with hydrogen or lower alkyl; R¹represents naphthalen-1-yl; naphthalen-2-yl; benzo[1,3]dioxol-5-yl;benzyl, or mono-, di-, or tri-substituted benzyl substituted in thephenyl ring independently with lower alkyl, lower alkyloxy,trifluoromethyl, halogen, cyano; phenyl, or mono-, di- ortri-substituted phenyl, substituted independently with lower alkyl,lower alkyloxy, trifluoromethyl, halogen, cyano; R² represents hydrogen,lower alkyl, aryl or forms with R¹ a styryl group of E or Z geometry,whereby the phenyl ring in the styryl group may be mono-, di- ortri-substituted phenyl, substituted independently with lower alkyl,lower alkyloxy, trifluoromethyl, halogen, cyano; R³, R⁴, R⁵ and R⁶independently represent hydrogen, cyano, hydroxy, lower alkyloxy,aralkyloxy, lower alkenyloxy, and R⁵ additionally represents R⁷R⁸NCO; R⁴and R⁵ together may form with the phenyl ring a five- or a six-memberedring containing one or two oxygen atoms; R⁷ and R⁸ independentlyrepresent hydrogen, lower alkyl, aryl, aralkyl, or together with the Nform a pyrrolidine, piperidine, or morpholine ring; and optically pureenantiomers or diastereomers, mixtures of enantiomers or diastereomers,diastereomeric racemates, and mixtures of diastereomeric racemates; aswell as their pharmaceutically acceptable salts, solvent complexes, andmorphological forms.
 2. A compound of general formula 2,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Z, and n have the meaning given ingeneral formula 1 of claim
 1. 3. A compound of general formula 3,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z have the meaning given ingeneral formula 1 of claim
 1. 4. A compound of general formula 4,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given ingeneral formula 1 of claim
 1. 5. A compound of general formula 5,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given ingeneral formula 1 of claim
 1. 6. A compound of general formula 6,

wherein R1, R2, R3, R4, R5, R6, Y, Z, and n have the meaning given ingeneral formula 1 of claim
 1. 7. A compound of general formula 7,

wherein R1, R3, R4, R5, R6, X, Y, Z, and n have the meaning given ingeneral formula 1 of claim
 1. 8. A compound of general formula 8,

wherein Ph is phenyl; mono-, di- or tri-substituted phenyl, substitutedindependently with hydrogen, lower alkyl, lower alkyloxy,trifluoromethyl, halogen, or cyano; R³, R⁴, R⁵, R⁶, X, Y, Z, and n havethe meaning given in general formula 1 of claim
 1. 9. A compound ofgeneral formula 9,

wherein R1, R2, X, Y, Z, and n have the meaning given in general formula1 of claim
 1. 10. A compound of general formula 10,

wherein R1, R2, X, Y, Z, and n have the meaning given in general formula1 of claim
 1. 11. A compound of general formula 11,

wherein R1, R2, X, Y, Z, and n have the meaning given in general formula1 of claim
 1. 12. A compound of general formula 12,

wherein R1, R2, R3, R4, R5, R6, X, Y, and n have the meaning given ingeneral formula 1 of claim
 1. 13. A compound of general formula 13,

wherein R1, R2, R3, R4, R5, R6, X, Y, and n have the meaning given ingeneral formula 1 of claim
 1. 14. A compound of general formula 14,

wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, and n have the meaninggiven in general formula 1 of claim
 1. 15. A compound of general formula15,

wherein the 1 position of the 1,2,3,4-tetrahydroisoquinoline ring systemhas the R absolute stereochemical configuration; R1, R2, R3, R4, R5, R6,X, Z, and n have the meaning given in general formula 1 of claim
 1. 16.A compounds of general formula 16,

wherein R3, R4, R5, and R6 are independently hydrogen or lower alkyloxy;R1, R2, and Z have the meaning given in general formula 1 of claim 1.17. The compounds according to claim 1 selected from the groupconsisting of1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3-Fluoro-4-methoxy-benzyl6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(3-Fluoromethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea;1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea;1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[(E)-2-(2,4-Difluoro-phenyl)vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(2,3-Dfluoro-phenylyethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolinyl)-urea;1-(2-{1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2(2,5-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(3,5-Bis-trifluoromethyl-phenylethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{1-[2-(4-Fluoro-phenyl)ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolinyl)-urea;1-(2-{6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-(2-{6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea;1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethy]-3-(2-methyl-quinolin-4-yl)-urea;1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-pyridin-4-yl-urea;1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea;1-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea;1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea;1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-pyridin-4-yl-urea;1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea;1-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea;1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea;1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea;1-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea;1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[2-(6,7-Dimethoxy-1-phenoxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea;1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea;1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea;1-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolinyl)-urea;1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridinyl-urea;1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{3-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea;1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea;1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea;1-{3-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea;1-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-quinolin-yl-urea;1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-quinolin-4-yl-urea;1-[2-(1-Benzhydryl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea;1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea;1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea;1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-quinolin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea;1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea;1-{2-[(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea;1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid methylamide;1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid propylamide;1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid dimethylamide;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(7-methyl-[1,8]naphthyridin-4-yl)-urea;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea;1-[2-(Benzyl-methyl-amino)-pyridinyl-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea;1-[2-(Benzyl-methyl-amino)-6-methyl-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-[2-(methyl-phenyl-amino)-pyridinyl]-urea;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-pyrrolidin-1-yl-pyridin-4-yl)-urea;1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methylamino-1-yl-pyridin-4-yl)-urea;Quinolin-4-yl-carbamic acid2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethylester; Quinolin-4-yl-carbamic acid2-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl ester;Quinolin-4-yl-carbamic acid2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethylester; Quinolin-4-yl-carbamic acid3-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester;Quinolin-4-yl-carbamic acid3-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl]-propylester; Quinolin-4-yl-carbamic acid3-[1-(3,4-difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester; Quinolinyl-carbamic acid3-[1-(3,4-dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester; and Quinolin-4-yl-carbamic acid3-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester; and pharmaceutically acceptable salts thereof.
 18. APharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier and/or and adjuvant.